This invention relates to a process for producing a 3-tetrazolyl-pyrido[1,2-a]pyrimidin-4-one derivative which is useful as an antiallergy agent.
3-Tetrazolyl-pyrido[1,2-a]pyrimidin-4-one derivative represented by the formula: ##STR1## wherein R.sup.1 and R.sup.3 are independently a hydrogen atom or a lower alkyl group; and R.sup.2 and R.sup.4 are independently a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group or ##STR2## (R.sup.5 is a hydrogen atom or a hydroxyl group; R.sup.6 is a hydrogen atom or an acyl group; and R.sup.7 is a hydrogen atom, a lower alkyl group or an allyl group) (hereinafter abbreviated as "compound [I]") and salts thereof are known as drugs having antiallergy activity, and various antiallergy agents containing them as active ingredient have come into wide use.
As a process for producing such a compound, there has most generally been employed a process which comprises reacting a compound of the formula: ##STR3## wherein R.sup.1 through R.sup.4 are as defined above, or the formula: ##STR4## wherein R is a methyl group or an ethyl group; and R.sup.1 through R.sup.4 are as defined above, with a hydrazoic acid salt of wide variety to carry out conversion to a tetrazole ring, as disclosed, for example, in Japanese Patent Appln. Kokai (Laid-Open) No. 63-246374 and U.S. Pat. Nos. 4,122,274 and 4,816,459. As the hydrazoic acid salt, aluminum azide or ammonium azide is used in the reaction. As described in J. Am. Chem. Soc., 80, 3908-3911 (1958), when sodium azide is used alone in a method for forming a tetrazole ring from a nitrile group, a reaction at a high temperature for a long period of time is required and moreover the yield is low. Therefore, it is considered effective to carry out the conversion to a tetrazole ring by converting sodium azide to ammonium azide, aluminum azide or the like by using ammonium chloride, aluminum chloride or the like together with sodium azide. This method is employed also in the above-mentioned prior art references.
However, even when ammonium chloride, aluminum chloride or the like is thus co-used, the yield is not high by any means, namely, its maximum is a little over 50%, and the co-use of these compounds gives birth to several evils. For example, when ammonium chloride is co-used, sodium azide acts as ammonium azide, which is very highly sublimable and escapes from the system on reaction at a high temperature for a long period of time. Therefore, sodium azide and ammonium chloride should be used in large excess, so that the efficiency is very low. When aluminum chloride or the like is co-used, sodium azide acts as a polyvalent metal salt of hydrazoic acid, such as aluminum azide in the system. The polyvalent metal salt of hydrazoic acid, such as aluminum azide is a very dangerous explosive compound, and therefore its handling requires extreme care and skill. When such a polyvalent metal salt is used in the reaction, a large amount of azide group which does not participate in the conversion to a tetrazole ring remains after the reaction, resulting in generation of a large amount of hydrazoic acid. Therefore, an air pollution problem is caused, and furthermore, disposal of metal wastes due to aluminum, etc. is required.
Accordingly, for making such methods practicable (industrial), there should be considered not only the low yield but also the problem of working environment and assurance of the safety of workers, the problem of facilities for preventing air pollution, the problem of time, labor and the like required for disposal of industrial wastes, etc. Thus, it is very desirable to improve the methods.